Summary of Work: The highly receptor selective delta-opioid di- and tripeptide antagonists containing the Dmt-Tic pharmacophore were hydrophobically modified at the N- and C-termini. For the most part, the protonated nitrogen consisted of either a secondary or teriary amine. Whereas modifications at the N-terminus provided a role for the protonated N (only a few peptides demonstated activity), most C- terminal substituents exhibited minor effects on delta binding. On the other hand, as the hydrophobicity of alterations rose mu binding increased in some cases by 3,000-fold to produce receptor neutral or mu-selective compounds. The crystalline structure of N,N(dimethyl)Dmt- Tic-OH revealed that a bioactive peptide was completely superimposable on the theoretical model of cyclo(Dmt-Tic) or H-Dmt-Tic-OH developed by molecular dynamics paradigms with a rms of 0.3 A. Furthermore, the N,N- dimethylated amide analogue was a potent inverse agonist in the S-35 GTP labelling of G proteins as recorded by the reversal of base line established by naltrindole (a non-peptide delta opiate standard antagonist) or H-Dmt-Tic-OH. Another new feature of these molecules was the strong inhibition of hMDR-1 P-glycoprotein by several hydrophobically modified Dmt-Tic analogues. In particular, one peptide which lacked strong biological activity and verified by an unusual X- ray crystalline structure, could be applied to the treatment of tumors harboring this protein as a chemosensitizing agent. And lastly, at least two analogues were active systemically to reverse delta-opioid induced analgesia. The key residue in these highly active peptides is Dmt in combination with Tic. However, new Dmt di- and tripeptides with additional aromatic centers, with and without Tic, are currently being investigated. In fact, a new group of peptides are under development with our collaborators in Japan exhibit potent mu agonist activity and high turn over that would permit a possible function in the control of cancer pain without addiction. - Delta- and mu-opioid antagonists and agonists; opioids; receptor binding; brain synaptosomes; peptide synthesis.